Search

Results from the online survey on diagnostic considerations and terminology in cases of possible systemic juvenile idiopathic arthritis. (DOCX 22Â kb)

Consensus process for the development of statements on the management of systemic juvenile idiopathic arthritis. AID-Net; autoinflammatory disease registry; ICON-JIA, inception cohort for patients with new-onset juvenile idiopathic arthritis; SJIA, systemic juvenile idiopathic arthritis. (DOCX 21 kb)

Objective: The objective was to evaluate the 25(OH) vitamin D (25(OH)D) status of patients with juvenile idiopathic arthritis (JIA) and determine whether the 25(OH)D level is associated with disease activity and the course of JIA. Methods: Patients ≤ 16 years of age with recently diagnosed JIA (< 12 months) were enrolled in the inception cohort of patients with newly diagnosed JIA (ICON), an ongoing prospective observational, controlled multicenter study started in 2010. Clinical and laboratory parameters were ascertained quarterly during the first year and half-yearly thereafter. Of the 954 enrolled patients, 360 patients with two blood samples taken during the first 2 years after inclusion and with follow up of 3 years were selected. The serum 25(OH)D levels were determined and compared with those of subjects from the general population after matching for age, sex, migration status and the month of blood-drawing. Results: Nearly half of the patients had a deficient 25(OH)D level (< 20 ng/ml) in the first serum sample and a quarter had a deficient level in both samples. Disease activity and the risk of developing JIA-associated uveitis were inversely correlated with the 25(OH)D level (β = - 0.20, 95% CI - 0.37; 0.03, hazard ratio 0.95, 95% CI 0.91; 0.99, respectively). Conclusion: In this study, 25(OH)D deficiency was common and associated with higher disease activity and risk of developing JIA-associated uveitis. Further studies are needed to substantiate these results and determine whether correcting 25(OH)D deficiency is beneficial in JIA. CA extern

Key components of clinical case scenarios used for the online survey. (DOCX 29 kb)

Background Although several studies show that JIA-patients have significantly lower employment rates than the general population, the research on educational and occupational attainments in patients with juvenile idiopathic arthritis (JIA) remain conflicting most likely due to small sample sizes. Therefore, aim of this study is to compare the educational achievements and employment status of 3698 JIA-patients with the German general population (GGP). Methods “SEPIA” was a large cross-sectional study on the current status of a historic cohort of JIA-patients treated in a single center between 1952 and 2010. For the analyses of education and employment a sub-cohort was extracted, including only adult cases with a confirmed diagnosis of JIA (N = 2696). Participants were asked to fill out a standardized written questionnaire on education and employment. Outcome measures (education/unemployment) were directly standardized to the GGP using data obtained from the National Educational Panel Study 2013 (N = 11,728) and the German Unemployment Statistics 2012 of the Federal Statistical Office (N = 42,791,000). Results After age- and sex-standardization, 3% (95% Confidence Interval 1.9 to 4.1%) more of the JIA-patients (26%) than of the GGP (23%) had only reached primary education. In contrast, parents of JIA-patients had similar levels of education as parents in the GGP. With a standardized difference of 0.2% (95% CI: 0.16 to 0.19%), the unemployment rate in JIA-patients was slightly, but not significantly higher than in the GGP. Stratifying for disease duration and the current treatment status, differences were confirmed for persons diagnosed before 2001, whilst for patients diagnosed after 2000, differences were found only in JIA-patients with ongoing disease. Medium and high educational achievements did not differ statistically significant between JIA patients and the GPP. Conclusion Educational achievements in German JIA-patients are significantly lower than in the GGP. Furthermore we were able to identify a slightly higher level of unemployment, especially in those with still under treatment and longer disease duration. Better treatment options as well as further development of social support programs might help to overcome this lifelong secondary effect of JIA. Electronic supplementary material The online version of this article (doi:10.1186/s12969-017-0172-2) contains supplementary material, which is available to authorized users.

Background: Inflammatory bowel disease can develop with some rheumatic diseases in childhood, including juvenile idiopathic arthritis (JIA). Systemic onset JIA has not been connected to inflammatory bowel disease (IBD), but might be connected especially in the context of new treatments. Methods: [for full text, please go to the a.m. URL], 44. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 30. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 26. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

This paper deals with the issue of using ecological oils in the sliding pair of hydraulic and transmission systems working in the area of agriculture. The sliding pair included a B 60 bearing and a journal with contact surface made of 14 220 steel. The experimental tests were carried out with two oils: the Fuchs Plantohyd 46 S ecological oil and PP 80 reference oil (producer: Slovnaft) which is a commonly used lubricant in given conditions. The results of the experiments were statistically processed and based on them, friction coefficient and temperature, both depending on the test duration, was evaluated. Consequently, the weight loss and roughness change of both tribological elements were statistically processed.

Analysis of the ImmunoChip single nucleotide polymorphism (SNP) array in 2816 individuals, comprising the most common subtypes (oligoarticular and RF negative polyarticular) of juvenile idiopathic arthritis (JIA) and 13056 controls strengthens the evidence for association to three known JIA-risk loci (HLA, PTPN22 and PTPN2) and has identified fourteen risk loci reaching genome-wide significance (p < 5 × 10-8) for the first time. Eleven additional novel regions showed suggestive evidence for association with JIA (p < 1 × 10-6). Dense-mapping of loci along with bioinformatic analysis has refined the association to one gene for eight regions, highlighting crucial pathways, including the IL-2 pathway, in JIA disease pathogenesis. The entire ImmunoChip loci, HLA region and the top 27 loci (p < 1 × 10-6) explain an estimated 18%, 13% and 6% risk of JIA, respectively. Analysis of the ImmunoChip dataset, the largest cohort of JIA cases investigated to date, provides new insight in understanding the genetic basis for this childhood autoimmune disease.

Crude and age and sex-standardized comparison of the employment status of the SEPIA study population admitted to the GCPAR before 2001 and the German General Population. (DOCX 32 kb)

Age- and sex-standardized comparison of the educational achievements of the study population admitted to the GCPAR before 2001 and the GGP. (DOCX 49 kb)

Coloscopy results of the 3 patients, translated and summarized from the German original. (DOCX 23Â kb)

Crude and age- and sex-standardized comparison of the unemployment rate of the SEPIA study population and the Bavarian General Population. (DOCX 38 kb)

Supplementary clinical and laboratory data for the patients at time of diagnosis of sJIA. (DOCX 23Â kb)

Background Treatment response, remission rates and compliance in patients with polyarticular juvenile idiopathic arthritis (polyJIA) treated with adalimumab, etanercept, or tocilizumab were analyzed in clinical practice. Methods Data collected in the German BIKER registry were analyzed in patients with polyJIA who started treatment with approved biologics, adalimumab, etanercept or tocilizumab, from 2011 to 2015. Baseline patient characteristics, treatment response, safety and drug survival were compared. Results Two hundred thirty-six patient started adalimumab, 419 etanercept and 74 tocilizumab, with differences in baseline patient characteristics. Baseline Juvenile Disease Activity Score (JADAS)10 (mean ± SD) in the adalimumab/etanercept/tocilizumab cohorts was 12.1+/−7.6, 13.8 ± 7.1 and 15.1 ± 7.4, respectively (adalimumab vs etanercept, p = 0.01), and Childhood Health Assessment Questionnaire (CHAQ)-disability index scores was 0.43 ± 0.58, 0.59 ± 0.6 and 0.63 ± 0.55, respectively (adalimumab vs etanercept, p

Steam refining of non-debarked poplar wood with SO2 impregnation prior to steaming was investigated as pretreatment for enzymatic hydrolysis. Pretreatment conditions were varied in the range of 170°C–220°C, 3–30 min and 0.7–2.5% SO2 according to a factorial design. Predicted steaming conditions for highest carbohydrate yields after enzymatic hydrolysis were at 200°C, 15 min, and 2.5% SO2. The yield of glucose and xylose from control tests under these conditions was 43% representing an increase of 9% compared to results of former experiments without SO2 impregnation. Investigations on lignin extracted from the fibers revealed no distinct differences between pretreatment with and without SO2. No sulfonation occurred by the impregnation with SO2. Topochemical analyses of the fibers by cellular UV microspectrophotometry (UMSP) showed an inhomogeneous lignin distribution within the S2 of fibers after pretreatment without SO2 and local depositions of high UV-absorbing substances in the lumina of fibers and parenchyma cells. The lignin distribution of fiber cell walls after pretreatment with SO2 was more homogeneous with a preserved fiber network and only little amounts of deposited phenolic compounds in the lumina. Therefore, it might be concluded that the expulsion of lignin hinders the enzymes in accessing the cellulose.

Control of disease activity and recovery of function are major issues in the treatment of children and adolescents suffering from juvenile idiopathic arthritis (JIA). Functional therapies including physiotherapy are important components in the multidisciplinary teamwork and each phase of the disease requires different strategies. While in the active phase of the disease pain alleviation is the main focus, the inactive phase requires strategies for improving motility and function. During remission the aim is to regain general fitness by sports activities. These phase adapted strategies must be individually designed and usually require a combination of different measures including physiotherapy, occupational therapy, massage as well as other physical procedures and sport therapy. There are only few controlled studies investigating the effectiveness of physical therapies in JIA and many strategies are derived from long-standing experience. New results from physiology and sport sciences have contributed to the development in recent years. This report summarizes the basics and main strategies of physical therapy in JIA.

Die Behandlungserfolge bei Kindern und Jugendlichen mit rheumatischen Erkrankungen verbesserten sich in den letzten 15 Jahren erheblich bezuglich der Erkrankungsaktivitat. Zur Reduktion der weiterhin haufigen Funktionseinschrankungen ist es notig, neue Therapiekonzepte zu entwickeln. Die gezielte Integration des Sports in die Therapie spielt dabei eine zunehmende Rolle. Kinderrheumatologische Sporttherapiekonzepte nutzen den Sport in Abhangigkeit von der aktuellen Entzundungsaktivitat und den Interessen der Patienten in die Therapie. Ziel ist es, die Menge qualitativ gunstiger Bewegungen der Patienten zu steigern. Bei hoher Erkrankungsaktivitat soll dies unter der Voraussetzung niedriger Gelenkbelastungen, in inaktiven Phasen mit dosierten Gelenkbelastungen und in der Restitution mit Achtsamkeit beim Belasten geschehen. Anhand von Ergebnissen der 3D-Bewegungsanalyse und eines Fitnesstests wurde fur Kinder mit juveniler idiopathischer Arthritis ein PMW-Training („Praventives Mobilitatsworkout“) als Ubungsprogramm entwickelt. Dieses soll rehabilitativ und sekundarpraventiv in der inaktiven Phase zur Verbesserung der Beweglichkeit, der Kraft, der Stabilitat und der Balance der Patienten beitragen. Das Training dauert ca. 10 min und soll taglich durchgefuhrt werden. Die Schulsportteilnahme ist wunschenswert und sollte je nach Erkrankungsphase entschieden werden.

Time-lapse photography provides an attractive source of information about snow cover characteristics, especially at the small catchment scale. The objective of this study was to design and test a monitoring system, which allows multi-resolution observations of snow cover characteristics. The main aim was to simultaneously investigate the spatio-temporal patterns of snow cover, snow depth and snowfall interception in the area very close to the camera, and the spatio-temporal patterns of snow cover in the far range. The multi-resolution design was tested at three sites in the eastern part of the Austrian Alps (Hochschwab-Rax region). Digital photographs were taken at hourly time steps between 6:00 and 18:00 in the period November, 2004 to December, 2006. The results showed that the time-lapse photography allows effective mapping of the snow depths at high temporal resolution in the region close to the digital camera at many snow stake locations. It is possible to process a large number of photos by using an automatic procedure for accurate snow depth readings. The digital photographs can also be used to infer the settling characteristics of the snow pack and snow interception during the day. Although it is not possible to directly estimate the snow interception mass, the photos may indeed give very useful information on the snow processes on and beneath the forest canopy. The main advantage of using time-lapse photography in the far range of the digital camera is to observe the spatio-temporal patterns of snow cover over different landscape configurations. The results illustrate that digital photographs can be very useful for parameterising processes such as sloughing on steep slopes, snow deposition in gullies and snow erosion on mountain ridges in a distributed snow model. Copyright © 2011 John Wiley & Sons, Ltd.

ZusammenfassungDie Inzidenz des systemischen Lupus erythematodes (SLE) wird in Europa und Nordamerika zwischen 1 und 10 auf 100 000 pro Jahr angegeben. Davon sind etwa 10 % der Fälle medikamenteninduziert. Die Symptome des medikamenteninduzierten Lupus sind identisch mit denen des SLE, jedoch ist der Verlauf häufig milder. Er ist gekennzeichnet durch Symptome wie Arthralgien, Myalgien, Fieber, Pleuritis und Perikarditis. Eine schwere renale Beteiligung oder ZNS-Symptomatik ist normalerweise nicht vorhanden. Auch die dermatologischen Veränderungen wie Photosensitivität, Purpura oder Erythema nodosum sind im Allgemeinen milder. In der Labordiagnostik finden sich häufig eine leichte Zytopenie, erhöhte BKS sowie ANA mit einem homogenen Muster. Der Nachweis von Anti-Histon-Antikörpern wird mit einer Sensitivität von 67 % und Spezifität von 95 % für den medikamenteninduzierten Lupus angegeben (1). Die Pathogenese ist bisher nicht sicher geklärt. Mehr als 80 Pharmaka werden mit dem medikamenteninduzierten Lupus in Verbindung gebracht. Es wird angenommen, dass diese Medikamente die Genexpression in Immunzellen beeinflussen und eine Autoreaktivität ausgelöst wird (2). Nach Absetzen des auslösenden Medikaments sind die Krankheitssymptome innerhalb von einigen Wochen bis Monaten gut rückläufig. Die Titer der Autoantikörper fallen allmählich wieder ab. Grundsätzlich ist die medikamentöse Therapie identisch zum SLE, jedoch sind in den meisten Fällen niedrig dosierte Steroide oder nichtsteroidale Antiphlogistika ausreichend.

Zusammenfassung Hintergrund: Seit Einführung der TNF-Inhibitoren in die Therapie der juvenilen idiopathischen Arthritis (JIA) hat sich die Prognose für viele Patienten erheblich verbessert. Ziele und Methoden: Daten des deutschen JIA-Etanercept-Registers wurden in Jahreskohorten von 2000–2010 bzgl. Patientencharakteristika, Vorbehandlung, Begleittherapie und Krankheitsaktivität analysiert. Die Wirksamkeit der Therapie wurde anhand der PedACR30/50/70-Kriterien und Kriterien für inaktive Erkrankung und Remission analysiert. Sicherheitsbewertungen erfolgten auf der Basis von Berichten über unerwünschte Ereignisse. Ergebnisse: Von 2000 bis 2010 wurden 1335 mit Etanercept behandelte JIA-Patienten in das Register aufgenommen. Am häufigsten erhielten Patienten mit einer seronegativen Polyarthritis Etanercept. In den frühen Jahreskohorten lag der Anteil von Patienten mit einer systemischen JIA bei 26 %, zuletzt zwischen zwei und fünf Prozent. Demgegenüber stieg der Anteil von Patienten mit einer Enthesitis-assoziierten Arthritis von zwei Prozent auf 17 % an. Die initial aufgenommenen Patienten wurden zuvor mit zahlreichen Antirheumatika (Mittel 3,4) einschließlich Zytostatika vorbehandelt. Diese Anzahl reduzierte sich über die Jahre auf 1,3/Patient. In der initialen Patientenkohorte wurden Kortikosteroide bei 83 %, Methotrexat bei 95 % und andere DMARDs bei 45 % der Patienten begleitend eingesetzt. Diese Begleitmedikation verminderte sich bei der Patientenkohorte mit Behandlungsbeginn in 2010 auf 27 %, 67 % und zehn Prozent. Die mittlere Krankheitsdauer vor Behandlungsbeginn nahm von 6,1 Jahren (Median 4,5 Jahre) auf 3,4 Jahre (Median 1,9 Jahre) ab. Der Anteil der Patienten mit einem PedACR70-Score nach Abschluss der ersten zwölf Behandlungsmonate stieg von 57 % auf 74 % an. Eine inaktive Erkrankung innerhalb eines Jahres wurde bei 24 % der initialen Patientenkohorte dokumentiert, während sich diese Rate im Beobachtungsverlauf auf 54 % erhöhte. Die Gesamtzahl unerwünschter Ereignisse im ersten Jahr der Behandlung war konstant, während die Rate schwerwiegender unerwünschter Ereignisse von 0,13/Patient auf 0,02/Patient sank. Fazit: Bei JIA-Patienten wird eine Therapie mit Etanercept zunehmend früher begonnen. Es erfolgen weniger Vorbehandlungen und es werden weniger Medikamente begleitend eingesetzt. Dabei zeigt sich eine verbesserte Verträglichkeit mit weniger ernsthaften Nebenwirkungen und eine höhere Effektivität.

Objective Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease resulting in excessive interleukin-1 release. It is unknown whether demographic, clinical, or laboratory characteristics at the time of diagnosis may identify patients who are at high risk for severe disease activity. This study was undertaken to analyze clinical and laboratory features of MWS, compare genetically defined subcohorts, and identify risk factors for severe MWS. Methods A multicenter cohort study of consecutive MWS patients was performed. Parameters assessed included clinical features, MWS Disease Activity Score (MWS-DAS), inflammation markers, and cytokine levels. E311K mutation–positive patients were compared with E311K mutation–negative patients. Putative risk factors for severe MWS (defined as an MWS-DAS score of ≥10) were assessed in univariate analyses, and significant predictors were entered into a multivariate model. Results Thirty-two patients (15 male and 17 female) were studied. The most frequent organ manifestations were musculoskeletal symptoms and eye and skin disorders. Renal disease and hearing loss were seen in >50% of the patients. Genetically defined subcohorts had distinct phenotypes. Severe disease activity was documented in 19 patients (59%). Predictors of severe MWS identified at the time of diagnosis were female sex, hearing loss, musculoskeletal disease, increased erythrocyte sedimentation rate, and low hemoglobin level. Female sex and hearing loss remained significant after adjustment for age in a multivariate model (relative risk 1.8 and 2.6, respectively). Conclusion MWS patients at high risk for severe disease can be identified at the time of diagnosis. Female patients presenting with hearing loss have the highest likelihood of manifesting severe MWS and should be considered a high-risk group.

TNF inhibitors and other biologicals have greatly expanded the therapeutic options for juvenile idiopathic arthritis (JIA). While the efficacy of etanercept and adalimumab has been proven in randomized controlled clinical trials, their long-term safety remains the subject of ongoing investigations. Reports of leukaemia and tumours in children and adolescents treated with etanercept, infliximab and adalimumab have raised questions about an increased risk for malignancies, with lymphoma accounting for the largest group at 50% of all 48 malignancies reported by the FDA.Consequently, TNF inhibitors should be indicated under careful consideration of individual risk factors, such as increased family occurrence of malignancies, or pre-treatment with carcinogenic substances such as cyclophosphamide. This is particularly true for non-approved substances, and non-approved indications, and for combination therapy of TNF inhibitors with immunosuppressive drugs. On the other hand, however, treatment should not be stopped or started in any patient in whom treatment is necessary due to the current knowledge. Adequate patient information, surveillance and documentation of treatment in the registry of the GKJR is strongly recommended.

A greenhouse gas emissions inventory was conducted for Chicago and its metropolitan region for the years 2000 and 2005. Emissions of carbon dioxide, methane, nitrous oxide, hydrofluorocarbons, perfluorocarbons, and sulfur hexafluoride totaled 34.7 million metric tons of carbon dioxide equivalents (MMTC02e) in Chicago in 2000 with 91% of emissions attributable to the indirect emissions associated with electricity consumption, the direct emissions of natural gas use, and the direct emissions of the transportation sector. A portfolio of 33 potential emissions reduction strategies was analyzed that, implemented together, could meet Chicago's target of reducing greenhouse gas emissions to 25% below 1990 levels by 2020. The largest potential for reduction is found in the areas with the largest emissions—energy use in buildings and transport. Compared to its metropolitan region, Chicago is found to have existing transportation efficiencies on a per household basis that can be an example for other commun...

SummaryAlpha thalassaemia myelodysplastic syndrome (ATMDS) is an unusualcomplication of chronic myeloid malignancy that is associated with a strikingred cell phenotype. It represents an acquired form of a-thalassaemia thatmost commonly arises in the context of myelodysplasia. It has recently beenshown that this condition occurs in association with somatic mutations of aknown X-encoded trans-acting regulator of a globin gene (HBA) expression,ATRX. There is an unexplained, strong male preponderance of individualswith the ATMDS phenotype with a >5:1 male–female ratio and furthermore,all the somatic ATRX mutations described to date have been in males. Herewe report the identification, in a single centre, of two females with ATMDSand mutations in the ATRX gene, proving that ATMDS associated with suchmutations may occur, albeit rarely, in females. It seemed possible that femalesmight be less likely to develop ATMDS if the inactivated copy of the ATRXgene (ATRX) became progressively re-activated throughout life. This studyruled out this hypothesis by investigating the pattern of ATRX inactivation ina cross-sectional analysis of normal females at ages ranging from newborn to90 years.Keywords: chromatin, DNA methylation, epigenetic disorders, haemoglobinregulation.

Background Methotrexate (MTX) intolerance is a frequent problem of long-term treatment in juvenile idiopathic arthritis (JIA). Mutations in the methylentetrahydrofolate reductase (MTHFR) gene may increase toxicity of MTX, potentially constituting an initial stimulus for this conditioned response. The objective of this study was to investigate the relationship of common MTHFR gene mutations and occurrence of MTX intolerance in pediatric patients with JIA treated with MTX. Methods Consecutive JIA patients on at least 3 months of MTX treatment were included in this study. Intolerance to MTX was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire, and MTX intolerance was defined as MISS values of ≥ 6. Presence of the two most common mutations in the MTHFR gene (C677T and A1298C) was tested using a PCR assay. Results were analyzed using descriptive and non-parametric statistics. Results 196 patients were included (73 % female). Of those, 93 (46 %) showed MTX intolerance. 168 patients were genotyped for C677T and A1298C. MTX intolerance was not found to be significantly more frequent among patients with hetero- and homozygous or homozygous mutations C677T or A1298C compared to wild type or heterozygous mutations. Analysis of the correlation between numbers of mutations in these two loci to the MISS score did not yield a statistically significant correlation. Conclusion Mutations in the MTHFR gene were not found to be significantly more frequent in JIA patients intolerant to MTX. Toxicity associated with the MTHFR gene seems to result from mechanisms different to those involved in clinical MTX intolerance. Electronic supplementary material The online version of this article (doi:10.1186/s12969-016-0071-y) contains supplementary material, which is available to authorized users.

Patient characteristics (unweighted as reported in BIKER). (DOCX 17 kb)

Zur Verbesserung von Patientensicherheit, Qualitat, Rechtzeitigkeit von Interventionen, Effektivitat und Versorgungsgerechtigkeit muss die Sektorierung des Gesundheitswesens uberwunden und eine patientinnen- und patientenzentrierte Versorgung implementiert werden. Ein wesentliches Instrument hierfur sind einrichtungsubergreifende Elektronische Patientenakten (eEPA), in denen die verteilt erhobenen und gespeicherten Behandlungsinformationen zusammengefuhrt und sachgerecht den beteiligten Akteurinnen und Akteuren auf Basis eines differenzierten Rechtemanagements zur Verfugung gestellt werden. Struktur und Semantik solcher Aktensysteme mussen in hinreichender Weise die Gegebenheiten der medizinischen Domane berucksichtigen. Die Funktionalitat muss uber die reine Verwaltung von Informationen hinausgehen und zum Beispiel das Behandlungsprozess- und Case-Management oder die Entscheidungsfindung unterstutzen. Letztendlich sollte eine eEPA auch integriert die Arzt-Patient-Kooperation unterstutzen und als Basis fur Zweitmeinungseinholungen zur Verfugung stehen.

Drug survival during treatment with etanercept, adalimumab or tocilizumab (combined cohorts) depending on the concomitant use of methotrexate, weighted Kaplan-Meier analyses weighted by an inverse probability of treatment estimated by a generalized propensity score. No significant differences were found between the two groups. (PPT 74 kb)

Pediatric ACR30/50/70/90 improvement in patients receiving etanercept, adalimumab or tocilizumab as a first-line or second-line biologic agent. (PPT 172 kb)

Intake and duration of rheumatic drugs. (DOCX 28 kb)

Table S3. Demographic and clinical data of study participants; patients where MTHFR testing was available. Table S4. Influence of demographic and clinical data on MTX intolerance; patients where MTHFR testing was available. (DOCX 35 kb)

Background: IL-12p40 plays an important role in the activation of the T-cell lines like Th17 and Th1-cells. Theses cells are crucial in the pathogenesis of juvenile idiopathic arthritis. A polymorphism in its promoter region and the genotype IL12p40 pro1.1 leads to a higher production of IL-12p40. We studied whether there is a difference in the distribution of the genotype in patients with JIA and the healthy population. Methods: In 883 patients and 321 healthy controls the IL-12p40 promoter genotype was identified by ARMS-PCR. Results: There is no association of IL-12p40 pro polymorphism neither in patients with JIA compared to controls nor in subtypes of JIA compared to oligoarthritis. We found a non-significant tendency of a higher prevalence of the genotype pro1.1 in systemic arthritis (32.4 %) and in rheumatoid factor negative polyarthritis (30.5 %) and a lower pro1.1 genotype in persistent oligoarthritis (20.7 %) and in enthesitis-related arthritis (17 %). Likelihood of the occurrence of genotype IL12-p40 pro1.1 in patients with systemic arthritis (OR 1.722, CI 95 % 1.344-2.615, p 0.0129) and RF-negative polyarthritis (OR 1.576, CI 95 % 1.046-2.376, p 0.0367) compared to persistent oligoarthritis was significantly higher. This was also true for comparison of their homozygous genotypes IL-12p40 pro 1.1 and 2.2 in systemic arthritis (OR 1.779, CI 95 % 1.045-3.029, p 0.0338). However, in Bonferroni correction for multiple hypothesis this was not significant. Conclusion: A tendency of a higher prevalence of the genotype IL-12p40 pro1.1 in systemic arthritis and in rheumatoid factor negative polyarthritis was observed but not significant. Further investigations should be done to clarify the role IL-12p40 in the different subtypes of JIA.

Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 x 10(-17), odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 x 10(-5), OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 x 10(-16), OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11-HLA-DQA1*05-HLA-DQB1*03 haplotype [6.4 x 10(-17), OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.

Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin-encoding MEFV mutations. Patients present with recurrent but self-limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil-derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF.Neutrophils from FMF patients carrying the p.M694V mutation (1 compound heterozygous and 5 homozygous) and neutrophils from 4 healthy control subjects were purified and stimulated in vitro. Neutrophil secretion of S100A12, interleukin-18 (IL-18), IL-1β, and caspase 1 was determined. Based on these in vitro analyses, serum concentrations of S100A12, IL-18, and IL-1β were also analyzed in 128 clinically and genetically characterized patients with FMF.In vitro, unstimulated neutrophils from p.M694V-positive patients spontaneously secreted more S100A12, IL-18, and caspase 1 compared to neutrophils from healthy controls. Serum concentrations of S100A12 correlated with disease activity and genotype, with the levels being highest in homozygous patients and with compound heterozygotes displaying higher levels than heterozygotes. Compared to individuals negative for the p.M694V mutation, heterozygous, compound heterozygous, or homozygous p.M694V-positive patients had higher serum levels of S100A12 and IL-18 during inactive and subclinical disease.The FMF phenotype is known to be more severe in patients carrying the p.M694V mutation. This report describes 2 molecules secreted by unconventional secretory pathways, S100A12 and IL-18, whose concentrations correlated with clinical disease activity and genotype in patients with FMF. In this clinically and genetically heterogeneous disease, management of these surrogate markers might help to improve patient care and outcomes.

Background Several medications for treatment of Juvenile Idiopathic Arthritis (JIA) are considered to be carcinogenic. Therefore, the aim was to assess whether there is an association between therapeutic interventions and malignancies in JIA patients. Findings A nested case–control study was carried out within a retrospective cohort study of 3698 JIA patients diagnosed between 1952 and 2010. All 48 JIA patients with a diagnosis of a malignant tumour and up to four matched controls for each received a questionnaire about their use of medication. Subsequently treatment was compared between cases and controls and analyses performed for 37 cases and 125 controls (response 88.5 %). Treatment with DMARD (84 %) was most frequently used, followed by glucocorticoids (66 %) and immunosuppressives (65 %). Twenty percent reported to have ever been taking biologics. Medication use did not differ significantly between cases and controls. Conclusions Our results did not show an association between medications used and malignancies in JIA patients. Electronic supplementary material The online version of this article (doi:10.1186/s12969-016-0066-8) contains supplementary material, which is available to authorized users.

Background Patients suffering from juvenile idiopathic arthritis (JIA) frequently have affected ankle joints, which can lead to foot deformities such as pes planovalgus (JIA-PPV). Usually, JIA-PPV is diagnosed by examining the foot in non-weightbearing or in weightbearing, static condition. However, functional limitations typically appear during dynamic use in daily activities such as walking. The aim of this study was to quantify the pathophysiology of JIA-PPV in both static and dynamic condition, i.e. in upright standing and during the stance phase of walking using three-dimensional (3d) gait analysis. Methods Eleven JIA patients (age = 12y) with at least one affected ankle joint and fixed pes planovalgus (≥5°) were compared to healthy controls (CG) (n = 14, age = 11y). Kinematic and kinetic data were obtained in barefoot standing and walking condition (1.1–1.3 m/s) with an 8-camera 3d motion analysis system including two force-plates and one pressure distribution plate. All participants were prepared using reflecting markers according to the Oxford Foot and Plug-in-Gait Model. Results were compared using the Mann–Whitney-U-test and Wilcoxon signed-rank test (p

In several large phase II trials, low-dose treatment with the azanucleoside 5-aza-2'-deoxycytidine (decitabine, DAC) resulted in complete hematologic and cytogenetic responses in 23 and 31% of MDS patients, respectively. The question of induction of chromosomal instability by this demethylating agent was addressed by serial karyotypic analyses. 53/122 DAC-treated patients had all normal metaphases at time of treatment start. In 46/53 patients, sequential cytogenetic analyses were performed. 9/46 patients (20%) acquired clonal chromosomal abnormalities during follow-up (4/9 transient). 8/9 abnormalities were gains or losses of entire chromosomes. The rate and pattern of cytogenetic evolution are thus not higher than in historical MDS cohorts not receiving specific treatment.